Work

Timescale of FLASH Sparing Effect Determined by Varying Temporal Split of Dose Delivery in Mice

Year: 2025

Type: article

Abstract: Purpose To determine the timescale for ultra-high dose rate (UHDR) radiation delivery that dictates FLASH normal-tissue sparing and elucidate its relationship to in vivo oxygen dynamics. A split-dose experiment was used to determine the transition time below which the observation of the FLASH sparing effect is preserved. Methods and Materials A 25 Gy dose was split into two deliveries (12.5 Gy), with varied interruption times. Albino B6 mice received flank skin irradiation in eight groups: single-beam UHDR (25 Gy at 415 Gy/s), single-beam conventional dose rate (CDR) (25 Gy at 0.15 Gy/s), or split-beam delivery with two lower-dose UHDR beams (12.5 Gy at 415 Gy/s) separated by 0.1, 1, 5, 15, 25, or 120 seconds. Skin damage was scored daily for 31 days, with mixed-effects analysis comparing damage progression across cohorts. Real-time tissue pO 2 was monitored using the phosphorescence-lifetime probe Oxyphor PdG4. Radiolytic oxygen consumption per unit dose (g O2 ) and reoxygenation rates were quantified. Results Single-beam UHDR significantly spared skin versus CDR. In split-dose groups, this sparing effect showed a transition at longer inter-beam intervals. Damage progression remained significantly lower than CDR and comparable to single-beam UHDR (p>0.16) for interruptions < 15 seconds. Longer intervals progressively lost tissue sparing. Oximetry indicated an average tissue reoxygenation lifetime of 7.7 ± 1.1 s. At the delivery of the second beam, pO 2 remained lower when inter-beam times were shorter than the reoxygenation period but recovered fully for longer interruptions. g O2 values correlated with baseline tissue pO 2 . Conclusions Observation of the FLASH sparing effect requires delivery within a critical temporal window that is similar timescale to tissue reoxygenation kinetics. The transition time for loss of the FLASH sparing effect in skin roughly corresponds to a diffusion timescale for oxygen, from capillaries to the cells. While not conclusively demonstrating a mechanism, this unique finding supports the likelihood that local oxygen depletion or consumption underlies the FLASH tissue sparing effect observed in vivo , with important implications for clinical implementation and the timescale needed for multi-beam FLASH-RT.

Source: International Journal of Radiation Oncology*Biology*Physics

DOI: 10.1016/j.ijrobp.2025.09.052